Field of the Invention
The present invention generally relates to the chemical synthesis of substituted thiazole derivatives. Specifically, the present invention relates to the chemical synthesis of fatostatin A and its analogs or derivatives.
Description of the Related Art
Metabolic syndrome covers many cardiovascular risk factors including hypertension, dyslipidaemia, obesity, type 2 diabetes, pancreatic β-cell dysfunction, and atherosclerosis. A diet varying in fat or carbohydrate contents contributes to energy metabolism of animals including humans. Long chain fatty acids are major source of energy and important components of the lipids that comprise the cellular membranes. They are derived from food and synthesized de novo from acetyl-CoA. Cholesterol is also derived from food and synthesized from acetyl-CoA. The conversion of carbohydrates into acylglycerides through de novo fatty acid and cholesterol synthesis involves at least 12 and 23 enzymatic reactions, respectively. Expression levels of the genes encoding these enzymes are controlled by three transcription factors, designated sterol regulatory element-binding proteins (SREBPs), SREBP-1a, -1c and SREBP-2. These membrane-bound proteins are members of a class of the basic helix-loop-helix leucin zipper family of transcription factors. Unlike other leucin zipper members of transcription factors, sterol regulatory element-binding proteins are synthesized as an ER-membrane-bound precursor, which needs to be proteolytically released by two proteases bound to the Golgi membrane, Site-1 and Site-2 proteases, in order to activate transcription of target genes in the nucleus.
The proteolytic activation of sterol regulatory element-binding proteins is tightly regulated by sterols through the interaction with sterol regulatory element-binding protein cleavage-activating protein (SCAP), an ER-membrane-bound escort protein of sterol regulatory element-binding proteins. When sterols accumulate in the ER membranes, the SCAP/SREBP complex fails to exit the ER to the Golgi, and thereby the proteolytic processing of sterol regulatory element-binding proteins is suppressed. Sterol regulatory element-binding proteins are key lipogenic transcription factors that govern the homeostasis of fat metabolism.
Fatostatin is identified as an inhibitor of sterol regulatory element-binding protein activation. Fatostatin impairs the proteolytic activation of sterol regulatory element-binding proteins, thereby decreasing the transcription of lipogenic genes in cells. There is a recognized need in the for the development of efficient methods and strategies for producing substantially pure fatostatin derivatives or analogs in large quantities for gaining further insights into the regulation of sterol regulatory element-binding protein in order to develop drugs. The present invention fulfills this need.